Histocompatibility-2 Research Articles

Overcoming innate host resistance to vaccination: Employing a genetically distinct strain of murine cytomegalovirus avoids vector-mediated resistance to virally vectored immunocontraception

The laboratory strain of murine cytomegalovirus (MCMV), K181, has been successfully engineered as a vaccine expressing murine zona pellucida 3 (mZP3) for viral vectored immunocontraception (VVIC) in mice. However, certain laboratory strains of mice are resistant to infection with K181 and therefore demonstrate resistance to VVIC. Cmv1 is the best characterised innate resistance mechanism to MCMV and was first described in C57BL/6 mice. Resistance in C57BL/6 mice is due to early and strong activation of natural killer (NK) cells by an MCMV gene product, m157, that binds directly to the NK cell activating receptor Ly49H. In this study a wild strain of MCMV, G4, which expresses a variant m157 incapable of activating Ly49H, was engineered to express murine zona pellucida 3 (mZP3) and assessed for its ability to sterilise female C57BL/6 mice. When infected with K181-mZP3 female C57BL/6 mice remained fully fertile. In contrast, female C57BL/6 mice were sterilised by a single intraperitoneal inoculation of G4-mZP3. Infertility was induced by G4-mZP3 in three strains of mice that express Ly49H, on two different histocompatibility-2 (H-2) backgrounds. Finally, enhanced immunocontraception was observed in mice expressing H-2k mediated resistance to MCMV when infected with G4-mZP3 compared to K181-mZP3. These data indicate that when using viral vaccine vectors, variant vector strains may be used to circumvent powerful innate immune responses against the vector and promote effective vaccination. This study highlights the importance of vaccine vector genetics in vaccination strategies.

Histopathological features of murine systemic vasculitis caused by Candida albicans extract--an animal model of Kawasaki disease.

We examined the histopathological features of systemic vasculitis caused in mice by injection of a Candida albicans ( C. albicans) extract and investigated the principal genetic roles in the development of vasculitis. C. albicans extract was injected intraperitoneally for five consecutive days in the 1st and 5th weeks to CD-1, C57BL/6N, C3H/HeN, BALB/cAnN, DBA/2N and CBA/JN mice. At week 8, mice were killed, and histological examination was performed by light microscopy. Arteritis had developed in 66% of CD-1 mice. The extramural coronary arteries and aortic root close to the orifice of coronary arteries were most frequently involved. Histologically, the characteristic feature of the arteritis was proliferative and granulomatous inflammation accompanied by numerous macrophages, lymphocytes, plasma cells and neutrophils. Fibrocellular intimal thickening with destruction of the internal elastic lamina and media was also observed. Five mouse strains after injection of C. albicans extract were clearly classified into a resistant group (CBA/JN, DBA/2N and BALB/cAnN mice) and a sensitive group (C3H/HeN and C57BL/6N mice). The inbred mouse strains which showed the same histocompatibility-2 (H-2) haplotype exhibited a different susceptibility to development of vasculitis. This arteritis murine model shows unique histological features that have not been observed in other animal vasculitis models and it most closely resembles Kawasaki disease in humans. The genetic control of susceptibility to induction of vasculitis by the C. albicans extract is dependent to the mouse strains, but is not linked to the H-2 loci.

Glucocorticoid hormone effect on transplacental carcinogenesis and lung differentiation: influence of histocompatibility-2 complex.

In the mouse, the histocompatibility-2 (H-2) haplotype influences induction of lung and intestinal tumors by N-ethyl-N-nitrosourea (ENU) treatment of fetuses or infant mice. The differentiation of lung and intestinal epithelium is known to be regulated by glucocorticoids. We show that glucocorticoid-induced development of alveolar lung volume is H-2 influenced and that glucocorticoid treatment of fetuses also influences prenatal ENU induction of lung and intestinal tumors. These glucocorticoid effects on tumorigenesis are also H-2 influenced. The number of papillary lung tumors increased in B10 (H-2b) and decreased in B10.A (H-2a) mice. In the intestine, the number of tumors increased in H-2b females and decreased in H-2b males. In H-2a mice, the number of intestinal tumors was unchanged but their location was altered. We propose that the H-2 complex influences tumorigenesis in lung and small intestine by affecting the hormonal regulation of differentiation of target epithelial cells.

T(16: 17)43H translocation as a tool in analysis of the proximal part of chromosome 17 (including T-t gene complex) of the mouse.

SUMMARYLinkage relationships of three gene markers of chromosome 17, namely Brachyury (T), tufted (tf), and Histocompatibility-2 (H-2), to the break-point of T(16; 17)43H male sterile translocation were established. The following order was found: T−tf−T43H−H-2. In all cases the translocation break was found in cis to H-2k, haplotype, no recombinant being found among 218 backcross individuals examined. More than 60 viable and fertile animals trisomic for the proximal part of chromosome 17 (including T-t genetic complex) have been recovered among progeny of T43H/+ female translocation heterozygotes as a result of adjacent −2 disjunction at first meiotic division. Mutation tf has been assigned to band 17B in chromosome 17 by comparing the location of T190Ca and T43H genetic and cytological breakpoints. Recombination between centromere 17 and T43H break was reduced almost to zero in the presence of Rb(16.17)7Bnr translocation. The unexpected restoration of male fertility was observed in T43H/Rb7Bnr hybrids (T43H/+ males being completely sterile) which made it possible to prepare the first homozygotes for T43H male–sterile translocation. Direct estimation of chiasma frequencies in centromere 17−T43H region indicated an 11 cM distance between the centromere 17 and the proximal end of t12 haplotype. The significance of centromere −t (or H-2) distance on the predictable restrictions of the possible haploid manifestation of T-t or H-2 gene products on sperm membrane is discussed.

Purification and chemical characterization of papain-solubilized histocompatibility-2 antigens from mouse liver.

A large scale purification of histocompatibility-2 (H-2) antigens from mouse liver is described. The antigens were solubilized by a limited papain digestion of a crude preparation of liver membranes (strain A/J) and purified by ion exchange chromatography, gel filtration, affinity chromatography, and isoelectric focusing. The overall degree of purification of H-2Kk was 1,300-fold and that of H-2Dd was 1,500-fold; approximately 8 mg of purified H-2a antigens were obtained from 1 kg of liver. The purification was followed by a sensitive radioimmunoassay in which H-2a-containing fractions were used to inhibit the binding of 125I-labeled H-2a to appropriate antisera. H-2Dd and H-2Kk co-purified through all the steps but the concentration of H-2Kk was 2- to 3-fold higher than that of H-2Dd in the liver homogenate as well as in the purified H-2 preparation. beta 2-microglobulin was initially present in a 3- to 10-fold excess over H-2 in the liver homogenate, but the purified H-2 preparation contained approximately 2 mol of alloantigenic heavy chain/mol of beta 2-microglobulin. Isoelectric focusing and disc-gel electrophoresis showed a charge heterogeneity of H-2, with a mean isoelectric point of pH 4.9. Electrophoresis on sodium dodecyl sulfate gels showed one band. Denaturing conditions were required to remove beta 2-microglobulin and small amounts of impurities from H-2. The amino acid sequence of the first 27 residues of the isolated heavy chains was determined.

Genetic control of cytolytic T-lymphocyte responses. I. Ir gene control of the specificity of cytolytic T-lymphocyte responses to trinitrophenyl-modified syngeneic cells.

The ability of cytotoxic T lymphocytes (CTL) induced in vitro to trinitrophenyl (TNP)-modified syngeneic cells to cross-reactively lyse a TNP allogeneic spleen target varies among inbred mouse strains. The cross-reactive CTL phenotype was found to be histocompatibility 2 (H-2) linked and to be dominant in F1 hybrid mice. All strains investigated demonstrated cross-reactivity except for some strains bearing portions of the H-2k haplotype. The gene(s) controlling this response maps to the K and/or I-A region of the H-2 complex. We have termed the immune response (Ir) gene responsible for controlling the specificity of CTL induced to TNP-modified syngeneic cells Ir-X-TNP.

Cleft palate susceptibility linked to histocompatibility-2 (H-2) in the mouse

Data have been obtained indicating that cortisone-induced cleft palate in the mouse is linked to theH-2 a complex. Cortisone (2.5 mg) was administered to pregnant females on days 11 through 14 of pregnancy. On day 17 of pregnancy, the fetuses were inspected for cleft palates. Sham experiments were done by injecting sterile saline instead of cortisone. The inbred strains, A/J and C57BL/6, and the congenic strains C57BL/10ScSn and B10.A were tested for susceptibility to cleft palate. The clefting frequency was also observed in hybrids of the congenic strains. The A/J and B10.A strains showed a characteristic high susceptibility to cleft palate (i.e., 99% and 81% incidence of cleft palate, respectively) after teratogenic treatment. The C57BL/6 and C57BL/ 10ScSn demonstrated a significant resistance to the teratogen (i.e., 25% and 21 % incidence of clefting, respectively). The teratogenic treatment of congenic hybrids indicated that maternal influences significantly affected the incidence of cleft palate formation. The maternal influence appeared to depend upon the specificH-2 haplotype of the mother.

Genetic association between H-2 gene and testosterone metabolism in mice.

SEVERAL characters involved in sexual dimorphism or male reproductive performance are influenced by genetic factors that are linked with the histocompatibility-2 (H-2) system of the mouse. These factors influence sperm cell production and function1–4 interstrain differences in relative weights of vesicular gland and testis4,5, immune response to the male-specific histocompatibility antigen6,7 and an androgen-dependent allotypic serum protein designated Slp8. Our finding of an H-2 linked gene influencing the size of such male hormone-dependent organs, as is the vesicular gland and testis, suggested that the amount of testosterone in plasma may be influenced by an H-2 linked gene. Whereas the genetic control of some hormonally determined traits is considered to be polygenic9,10, other data indicate some endocrine variation is due to allelic substitution at a single locus or very few loci11–14. These genes in the mouse genome have not yet been located.

PECULIAR IMMUNOBIOLOGY OF BONE MARROW ALLOGRAFTS

F(1) hybrid mice are capable of rejecting inbred parental strain bone marrow grafts after a single lethal exposure to X-rays. The incompatibility is genetically controlled by the Hybrid-histocompatibility-1 (Hh-1) locus in or near the D end of the Histocompatibility-2 (H-2) region. The onset of parental graft rejection begins 9-12 hr after transplantation and is completed by 24 hr. Maturation of hybrid resistance does not occur until the 22nd day of life. In adults, the resistance to parental marrow grafts can be temporarily abrogated or weakened by administration of cyclophosphamide or dead cultures of Corynebacterium parvum, acute supralethal exposures to radiation, or by split-dose irradiation with 6-37-day intervals. Parental marrow grafts elicit a transplantation reaction in irradiated F(1) mice which is indistinguishable from that elicited in irradiated allogeneic (H-2-incompatible) hosts. Because of this immunogenetic similarity, the following question is raised: are the same or different alloantigens responsible for rejection of parental and allogeneic marrow grafts? In the first case, Hh-1 alleles would be recessive determinants of tissue-specific transplantation antigens, whereas in the second case they would be the determinants of parental- and tissue-specific antigens subject to genetic suppression in Hh-1 heterozygotes. Although the available evidence is not conclusive in excluding one of the two possibilities, it favors the concept that allograft reactivity to hemopoietic cells is elicited by recessive tissue-specific antigens.

Tooth transplantation in the mouse. II. The role of the histocompatibility-2 (H-2) system in tooth germ transplantation

Allogeneic skin grafts transplanted on recipients presensitized with allogeneic tooth germs showed an accelerated rejection pattern. Apparently, developing teeth contain antigens of the major histocompatibility system, and these antigens are able to elicit a strong allograft reaction in the recipient.

Private and public antigens of the mouse H-2 system.

IT was observed rather early in the history of the mouse histocompatibility-2 (H-2) system that some antigens of the system are limited to only one or very few H-2 alleles, whereas others are shared by several alleles1. Antigens with limited distribution were called “private”, as opposed to “general” antigens present in many different H-2 alleles2. It has been tacitly assumed that the distinction between private and general antigens (the latter will be called “public” here) is an artificial one and that the difference between, them would disappear when new strains and new H-2 alleles were analysed. This, however, proved not to be the case. So far H-2 alleles of some seventy strains and stocks have been determined, and the distinction into private and public antigens still holds. It can be argued, of course, that because most of the strains of the laboratory mouse are related to each other in their origin3, the differences in frequencies of individual H-2 antigens are still only apparent.

Histocompatibility-2 (H-2) polymorphism in wild mice.

Red blood cells of 40 wild mice captured at four different locations in the Ann Arbor area were typed for the presence of 15 different H-2 antigens by direct hemagglutination test. Fifteen different phenotypes were found and all were different from those determined by known H-2 alleles of the laboratory mice. Great similarity between phenotypes of mice from the sane location was observed. This is interpreted as further evidence for the deme structure of natural mouse population.

A sex-limited serum protein variant in the mouse: inheritance and association with the H-2 region.

An alloantiserum produced in the mouse has been used to detect an antigen which is present only in male serum from certain inbred strains of mice, e.g., DBA/2J, A/J, and BALB/c. Genetic tests reveal that the presence of this antigen is controlled by a dominant autosomal gene which is expressed only in males of the proper genotype. Test crosses and analysis of congenic resistant strains indicate close linkage between the sex-limited protein (Slp) and the histocompatibility-2 (H-2) region of linkage group IX. Analysis of seven intra-H-2 recombinant strains is consistent with the placement of the genetic determinant for Slp within the H-2 region in the same position as the Ss (serum substance) determinant. Immunological evidence suggests that the Slp antigenic sites reflect structural variation in the Ss component of mouse serum.

Murine histocompatibility-2 (H-2) alloantigens. Purification and some chemical properties of a second class of fragments (class II) solubilized by papain from cell membranes of H-2b and H-2d mice.

ADVERTISEMENT RETURN TO ISSUEPREVArticleNEXTMurine histocompatibility-2 (H-2) alloantigens. Purification and some chemical properties of a second class of fragments (Class II) solubilized by papain from cell membranes of H-2b and H-2d miceKunio Yamane and Stanley G. NathensonCite this: Biochemistry 1970, 9, 6, 1336–1341Publication Date (Print):March 1, 1970Publication History Published online1 May 2002Published inissue 1 March 1970https://doi.org/10.1021/bi00808a006RIGHTS & PERMISSIONSArticle Views12Altmetric-Citations28LEARN ABOUT THESE METRICSArticle Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated. Share Add toView InAdd Full Text with ReferenceAdd Description ExportRISCitationCitation and abstractCitation and referencesMore Options Share onFacebookTwitterWechatLinked InReddit PDF (1 MB) Get e-Alerts Get e-Alerts

Comparison of the peptide composition of two histocompatibility-2 alloantigens.

The peptide composition of purified Histocompatibility-2 (H-2) reactive glycoprotein fragments from two murine strains allelic at the H-2 locus (H-2(b) and H-2(d)) were compared by a cellulose thin-layer peptide mapping micro technique. Approximately 70 per cent of the theoretical maximum number of peptides produced by cyanogen bromide cleavage and trypsin digestion were visualized by this technique. Most (38) of the peptides for the glycoproteins from these strains allelic for the H-2 locus were identical; however, three peptides of the H-2(b) and four peptides of the H-2(d) alloantigen were unique. The results demonstrate the remarkable similarity in protein structure between these two allelic products, but also show a small but reproducible difference in their peptide composition. The findings are consistent with the hypothesis that protein primary structure may determine wholly or in part their alloantigenic activities.

THE GENETIC CONTROL OF ANTIBODY SPECIFICITY

The immune response to a synthetic polypeptide built on multichain polyproline, poly-L-(Tyr,Glu)-poly-L-Pro-poly-L-Lys [(T,G)-Pro--L], in the offspring of a cross between DBA/1 and SJL mice is under a genetic control superficially similar to the one operating for the immune response to a similar synthetic polypeptide built on multichain polyalanine, poly-L-(Tyr,Glu)-poly-D,L-Ala-poly-L-Lys [(T,G)-A--L], in the offspring of a cross between CBA and C57 mice. In both cases, the genetic control is a quantitative trait in which the major gene(s) is (are) dominant and the trait is not linked to any of the known structural genes coding for mouse immunoglobulin heavy chains. However, the genetic control of response to (T, G)-Pro--L, designated immune response-3 (Ir-3), is qualitatively different from the one operating for (T,G)-A--L [immune response-1 (Ir-1)] in that it is not linked to the histocompatibility-2 (H-2) locus. A study of the immune response to a related polypeptide built on multichain polyproline, poly-L-(Phe,Glu)-poly-L-Pro-poly-L--Lys [(Phe, G)-Pro--L], in the DBA/1 x SJL cross has shown a genetic control of antibody specificity. F(1) x DBA/1 backcross anti-(Phe, G)-Pro--L sera segregate in their ability to bind (T,G)-Pro--L, and there is no linkage of anti-(T,G)-Pro--L binding capacity with the H-2(s) allele of the SJL grandparent. F(1) x SJL anti-(Phe, G)-Pro-L sera segregate in their capacity to bind poly-L-(Phe,Glu)-poly-D,L-Ala-poly-L-Lys [(Phe, G)-A--L] and the ability to bind (Phe, G)-A--L is clearly linked to the H-2(q) allele from the DBA/1 grandparent. Thus, in mice all responding well to a given antigen [(Phe, G)-Pro--L], the specificity of the antibodies produced [i.e., anti-(Phe,G) or anti-prolyl] is genetically determined. Cross-inhibition of binding m (DBA/1 x SJL)F(1) anti-(Phe,G)-Pro--L antisera indicates that the anti-(Phe,G) and anti-prolyl specificities are a function of two separate and largely non-crossreacting antibody populations.

Murine histocompatibility-2 (H-2) alloantigens. Purification and some chemical properties of soluble products from H-2b and H-2d genotypes released by papain digestion of membrane fractions.

ADVERTISEMENT RETURN TO ISSUEPREVArticleNEXTMurin histocompatibility-2 (H-2) alloantigens. Purification and some chemical properties of soluble products from H-2b and H-2d genotypes released by papain digestion of membrane fractionsAkira Shimada and Stanley G. NathensonCite this: Biochemistry 1969, 8, 10, 4048–4062Publication Date (Print):October 1, 1969Publication History Published online1 May 2002Published inissue 1 October 1969https://doi.org/10.1021/bi00838a023RIGHTS & PERMISSIONSArticle Views54Altmetric-Citations111LEARN ABOUT THESE METRICSArticle Views are the COUNTER-compliant sum of full text article downloads since November 2008 (both PDF and HTML) across all institutions and individuals. These metrics are regularly updated to reflect usage leading up to the last few days.Citations are the number of other articles citing this article, calculated by Crossref and updated daily. Find more information about Crossref citation counts.The Altmetric Attention Score is a quantitative measure of the attention that a research article has received online. Clicking on the donut icon will load a page at altmetric.com with additional details about the score and the social media presence for the given article. Find more information on the Altmetric Attention Score and how the score is calculated. Share Add toView InAdd Full Text with ReferenceAdd Description ExportRISCitationCitation and abstractCitation and referencesMore Options Share onFacebookTwitterWechatLinked InReddit PDF (3 MB) Get e-Alerts Get e-Alerts

Analysis of the histocompatibility-2 (H-2) locus of NZB mice.

Department of Genetics School of Medicine, Stanford University Palo Alto, California 2Czechoslovakia, Academy of Sciences, Institute of Experimental Biology and Genetics, Pargue, Czechoslovakia

USE OF "IMMUNOLOGICAL ENHANCEMENT" IN THE STUDY OF HISTOCOMPATIBILITY MUTATIONS.

The use of immunological enhancement in the detection of histocompatibility mutations at the histocompatibility-2 (H-2) locus was investigated. C57BL/10Sn (C57BL) and its isogenic resistant (IR) strains were used. Previous studies showed that enhancement of a tumor is antigenically specific and the enhancing antibody is a product of the H-2 antigens. The specificity of enhancement for the IR strains and the particular host-tumor combination best suited for enhancement were first investigated. DBA/1 strain as hosts gave the best results. No difference was found between various sarcomas. Complete specificity was lacking for strains C57BL and B10.D2 with active immunization. With passive immunization anti-B10.D2 serum enhanced tumors of B10.D2 strain and, partially, tumors of C57BL strain, whereas anti-C57BL serum enhanced only C57BL tumors. Mixture of tumor cells showed that anti-C57BL serum could enhance a small number of C57BL tumor cells in a large inoculum of B10.D2 cells; anti-B10.D2 serum enhanced both C57BL and B10.D2 tumor cells. The reason for this is discussed in relation to the antigenic constitution of the strains. Unlike B10.D2 strain, a third IR strain, B10.M, showed complete specificity for enhancement. Hybrid tumors of (C57BL × B10.D2)F1 were enhanced with anti-B10.D2 serum and not anti-C57BL serum. Hybrid tumors of (C57BL × B10.M)F1 were enhanced only when host mice were conditioned with antisera to both strains. The method of detection of mutations with enhancement is presented. By this method a large number of tumor cells were tested for mutant variants. No mutant variants could be isolated. The possible reason for lack of mutant variants at the H-2 locus is discussed. The lack of complete specificity for enhancement between some of the IR strains indicates that enhancement is not suitable for the study of mutations at the H-2 locus.